In vivo suppression of SIV-mediated immune activation

体内抑制 SIV 介导的免疫激活

• 批准号: 8603383
• 负责人: ANNA ALDOVINI
• 金额: $ 26.06万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-08 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603383
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Affect; Animals; Antigen-Presenting Cells; Apoptosis; Biological Preservation; Biopsy; CD4 Positive T Lymphocytes; Cause of Death; Cell surface; Cells; Cercocebus atys; Cercopithecus pygerythrus; Clinical Trials; Data; Dendritic Cells; Development; Disease; Disease Progression; Euthanasia; Freezing; Gene Activation; Gene Expression; Genes; Goals; HIV; HIV Infections; HIV-1; HLA-DR Antigens; Human; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interferons; Interruption; Intervention; Investigation; Kinetics; Laboratories; Lead; Light; Link; MAP Kinase Gene; MAPK14 gene; Macaca; Macaca mulatta; Maintenance; Maps; Mediating; Methods; Mitogen-Activated Protein Kinase Inhibitor; Molecular Profiling; Mucous Membrane; Outcome; Pathogenicity; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pilot Projects; Play; Population; Primates; Production; Protein Inhibition; Proteins; RNA Interference; Reporting; Resistance; Role; Route; SIV; Safety; Sampling; Serum; Serum Markers; Superantigens; Surface; T-Cell Depletion; T-Lymphocyte; Testing; Time; Viral Antigens; Viral Load result; Viral Proteins; Viremia; Virus; Virus Diseases; Work; chemokine; cytokine; drug development; human disease; immune activation; in vivo; inhibitor/antagonist; lymph nodes; macrophage; memory CD4 T lymphocyte; nonhuman primate; preclinical study; public health relevance; rectal; research study; response; transcription factor; treatment effect

DESCRIPTION (provided by applicant): Differences in levels of immunoactivation have been identified as the single more significant difference between AIDS susceptible and resistant species. Higher levels of immunoactivation correlate with HIV and SIV pathogenicity in certain species, possibly because increased CD4+ T cell immunoactivation would result in increased immunoactivation-mediated apoptosis, accompanied by CD4+ T cell depletion. Immunoactivation can be induced by a variety of mechanisms, including persistent stimulation of immune responses by viral antigens, and/or production of immunoactivating cytokines and chemokines. We have shown that HIV and SIV infections modulates primate APC and T-cell gene expression and that at least a subset of the IFN-stimulated genes (ISG), reprogrammed in infected human and RM iDC, are not affected by SIV infection in APC of AIDS resistant species. We had postulated that induction and maintenance of immune activation could depend on the induction by HIV or SIV of cell pathways leading to the production of immunoactivating cytokines and chemokines and have shown that this is the case in vitro. p38 MAPK, which has been reported to be activated in HIV and SIV infection, is key in the pathway of induction of ISG and is associated in vivo with the some of the pathology produced by HIV and SIV infection in AIDS susceptible primates. We identified how the viral protein Tat directly modulates cellular proteins that lead to the activation of the p38 MAPK pathway. As no effective drugs that block Tat activity exist and inhibitors of p38 MAPK are available and currently tested in human trials for other diseases, we intend to evaluate the effects of treating SIV-infected macaques with a p38 inhibitor that has been shown to reduce immune activation in trials for different human diseases. Our goal is to 1. To evaluate longitudinally the impact that in vivo PH-797804-mediated inhibition of p38 MAPK has on immune activation in four SIV-infected RM by evaluating as primary end points the gene expression profiles and expression of surface molecules linked to immune activation in RM PBMC, lymph node and rectal mucosa biopsies and the serum levels of inflammatory cytokines and chemokines; 2. to evaluate as secondary end points the effect that the treatment has on viral loads, preservation of central memory CD4+ T cells, and possibly on disease progression. This work could provide the rationale for testing p38 MAPK inhibitors in preclinical and clinical trials and for encouraging the development of effective Tat inhibitors.

描述（由申请人提供）：免疫激活水平的差异已被确定为艾滋病易感物种和耐药物种之间唯一更显着的差异。在某些物种中，较高水平的免疫激活与 HIV 和 SIV 致病性相关，可能是因为 CD4+ T 细胞免疫激活增加会导致免疫激活介导的细胞凋亡增加，并伴有 CD4+ T 细胞耗竭。免疫激活可以通过多种机制诱导，包括病毒抗原持续刺激免疫反应和/或产生免疫激活细胞因子和趋化因子。我们已经证明，HIV 和 SIV 感染调节灵长类 APC 和 T 细胞基因表达，并且在受感染的人和 RM iDC 中重新编程的至少一部分 IFN 刺激基因 (ISG) 不受 AIDS 抗性物种 APC 中 SIV 感染的影响。我们假设免疫激活的诱导和维持可能取决于 HIV 或 SIV 细胞途径的诱导，导致免疫激活细胞因子和趋化因子的产生，并且已经证明体外情况就是如此。据报道，p38 MAPK 在 HIV 和 SIV 感染中被激活，是 ISG 诱导途径的关键，并且在体内与 AIDS 易感灵长类动物中 HIV 和 SIV 感染产生的一些病理学相关。我们确定了病毒蛋白 Tat 如何直接调节导致 p38 MAPK 通路激活的细胞蛋白。由于不存在阻断 Tat 活性的有效药物，并且 p38 MAPK 抑制剂可用且目前正在针对其他疾病的人体试验中进行测试，因此我们打算评估用 p38 抑制剂治疗感染 SIV 的猕猴的效果，该抑制剂已在针对不同人类疾病的试验中被证明可以减少免疫激活。我们的目标是 1. 通过评估 RM PBMC、淋巴结和直肠粘膜活检中与免疫激活相关的基因表达谱和表面分子表达以及炎症的血清水平作为主要终点，纵向评估体内 PH-797804 介导的 p38 MAPK 抑制对四种 SIV 感染 RM 免疫激活的影响 细胞因子和趋化因子； 2. 作为次要终点评估治疗对病毒载量、中央记忆 CD4+ T 细胞的保存以及可能对疾病进展的影响。这项工作可以为在临床前和临床试验中测试 p38 MAPK 抑制剂以及鼓励开发有效的 Tat 抑制剂提供理论依据。